Manufacture of optically active menthones and menthols



Patented Apr. 8, 1941 UiTE MANUFACTURE OF OPTICALLY ACTIVE MENTHONES ANDMENTHOLS John William Blagllen and Walter Edward Huggett, Ilford,England No Drawing.

Application May '20, 1939, Serial N 0.

274,838. In Great Britain May 2-6, 1938 24) Claims.

This invention relates to the catalytic hydrogenation oflaevo-piperitone to produce menthones or menthols of full or very highoptical activity.

We have found that the catalytic hydrogenation of laevo piperitone bythe usual methods leads to products which are either optically inactiveor are of low optical activity owing to complete or partial racemisationwhich occurs during the hydrogenation to the menthone stage. Thus thehydrogenation of laevo-piperitol'le in presence of palladium (introducedin the form of palladium chloride) is found to yield a mixture ofmenthones which are racemised to the extent of 50 per cent.Hydrogenation in presence of a nickel or nickel-copper catalystcontaining magnesium as a promoter is found to yield ultimately amenthol mixture having only 65 per cent. of the theoretical opticalactivity.

This invention relates to a process for the Y catalytic hydrogenation oflaevo-piperitone in which racemisation is entirely prevented or great-1y reduced during hydrogenation by the choice of suitable conditions forthe hydrogenation.

One condition which tends to counteract racemisation. duringhydrogenation is the use of a catalyst fulfilling the followingconditions:

(a) It must not be appreciably basic or acidic, that is to say, whenextracted with water it must not impart to the water an appreciablebasic or acidic reaction; the extract water should show a pH value whichis between 5.0 and 10.0 and preferably is between 7.0 and 8.0; and

(b) It must not develop an appreciable basic or acidic reaction duringthe hydrogenation.

In particular, the catalyst should be free from even traces of freealkali. We have found that metal catalysts prepared by reduction fromthe precipitated metal carbon-ates invariably contain some free alkali.Catalysts suitable for use in the invention, however, can be preparedfrom the metal carbonate by first converting the carbonate into theoxide by heat and then washing the oxide with water until it is freefrom traces of caustic alkali and the washings have apH value within thelimits above: indicated. The presence of magnesium in small proportion(up to, say, about 5 per cent.) in the catalyst is not harmful.

Another condition which tends to avoid racemisation is the use of ahydrogenation temperature belowabout 140 C.

A further condition which counteracts racemisation during thehydrogenation of piperitone to menthones is the use of a suitableorganic solvent for the hydrogenation. Suitable solvents are thosecontaining oxygen and having a dielectric constant of at least about 15,for example. methyl alcohol, ethyl alcohol and ethylene glycol. The useof such a solvent is not essential in all cases but neverthelessconstitutes a desirable additional precaution. Such solvents, however,tend to prevent hydrogenation beyond the menthone stage and, when used,must therefore be removed after hydrogenation to the menthone stage whenit is desired to carry the hydrogenation to the menthol stage. However,the tendency towards racemisation is encountered mainly duringhydrogenation to the menthone stage and precautions against-racemisationare less necessary in the further hydrogenation to the menthol stage.

It may be advantageous to conduct the hyrogenation in stages, namely,first to carry the hydrogenation to the menthone stage and then tohydrogenate the product in a separate operaticn to the menthol stage.For thispurpose-the hydrogenation may be commenced in presence of asolvent of the kind abovedefinecl and, continued until absorption ofhydrogen ceases, the solvent then being removed and the hydrogenationcontinued.

We have found that the body hitherto regarded as pure laevo-piperitoneis in fact a mixture of laevo-piperitone with the racemate of piperitoneand in our U. S. Specification Serial No. 235,282 we have shown howthere may be obtained from such a mixture pure or substantially purelaevopiperitone having an optical rotation substantially higher thanthat hitherto regarded as the maximum for this body. Our discovery ofthe presence of the racemate of piperitone in the hitherto knownlaevo-piperitone reveals a further reason why the hydrogenation of thissubstance doesnot yield menthols of full optical activity.

The present invention permits the production of menthones and mentholshaving their full, or substantially full, optical activity from pure orSub-- stantially pure laevo-piperitone, that is to say, piperitonehaving an optical rotation of not less than about By hydrogenatingsubstantially pure laevoplperitone under the conditions of thisinvention there can be obtained a mixture of dextroneoisomenthol andlaevoleomenthol and from this mixture dextro-neoisomenthol andlaevoneomenthol having substantially their full optical activity maybeisolated by any known method,

for example, by the process Patent No. 1,932,131.

The dextro-neoisomenthol can be isomerised, for instance by a processsimilar to that described in U. S. Patents Nos. 1,811,711 and 1,811,777,to form a mixture of isomeric menthols containing the laevo-mentholcorresponding with the naturally occurring substance. This operationshould be conducted at a temperature lower than about 140 C. in order toavoid racemisation during the isomerisation. Preferably also thereshould be used for the isomerisation a hydrogenation catalyst fulfillingthe conditions hereinbefore indicated, advantageously a catalystcontaining some magnesium. From the mixture resulting from theisomerisation the substantially fully optically active laevo-menthol canbe isolated by known methods, for instance, by the process of U. S.Patent No. 1,932,131.

The separation of dextro-neoisomenthol from laevo-neomenthol containedin the hydrogenation product prior to the isomerisation is important forthe production of leavo-menthol of full or substantially full opticalactivity; this is because laevo-neomenthol corresponds in its asymmetrywith dextro-menthol and yields this body on isomerisation, so that theisomerisation of the mixture of dextro-neoisomenthol and laevoneomentholwould result in the formation of a certain quantity of inactive menthol.

It is to be understood that this form of the invention is not limited tothe use of laevopiperitone which has been obtained by the process of U.S. specification Serial No. 235,282 but esoribed in U. S.

is applicable to any substantially pure laevopiperitone. Furthermore,the invention is not limited to any particular conditions ofhydrogenation except such as avoid any appreciable racemisation duringthe hydrogenation.

The following examples illustrate the invention, the parts being byweight unless otherwise stated and the relationship between parts byweight and parts by volume being that which exist between the kilo andthe litre.

Example 1 430 parts by volume of a solution of nickel nitrate containing21 grams of nickel per 100 cc. and 100 parts by Volume of a solution ofchromium nitrate containing grams of chromium per 100 cc. are mixed andevaporated to dryness and the resulting mixture of nitrates is ignitedto the oxides by heating to about 350 C. The mixture of oxides is washedseveral times with distilled water until the Wash water is no longer ofa yellow colour (due to traces of sodium chromate) and has a pH value of7.5. The washed oxides are dried on a steam plate and then reduced in acurrent of hydrogen at 290 C. for several hours. 10 parts of thecatalyst thus prepared are added to a solution of 50 parts oflaevo-piperitone (having an optical rotation in 100 parts of methylatedspirit and the mixture is treated with hydrogen under a pressure of 100lbs. per square inch and at a temperature of 100 C. until absorption ofhydrogen ceases, which is the case when 1 molecular proportion ofhydrogen has been absorbed.

The catalyst and methylated spirit are then removed and the resultingmenthone is hydrogenated in the presence of a fresh catalyst preparedfrom a mixture of the carbonates of copper, nickel and magnesiumcontaining the metals in the ratio of Cu:Ni:Mg=10:10:1 by first ignitingthe mixture to the corresponding mixture of oxides by heating in an opendish to 300-350 C. washing the oxides with distilled water until thewash water has a pH value of not more than 10.0 (indicating the absenceof free alkali), drying and finally reducing the oxides in a hydrogenatmosphere at 240 C. for several hours. The hydrogenation is allowed toproceed under a pressure of lbs. per square inch and at a temperature of100 C. until a further molecular proportion of hydrogen has beenabsorbed. The catalyst is then removed by filtration.

By treating the hydrogenation product with ortho-phosphoric acid inpresence of petroleum ether according to the process described in U. S.Patent No. 1,932,131 there crystallises a phosphoric acid additioncompound which when decomposed yields dextro-neoisomenthol, havingv theoptical rotation (homogeneous) and a specific gravity at 20 C. of

The dextro-neoisomenthol thus obtained is then isomerised by the processdescribed in U. S. Patents Nos. 1,811,711 and 1,811,777, at atemperature of -140 in the presence of a coppernickel-magnesium catalystprepared in the manner above described. From the mixture of isomericmenthols so obtained, laevo-menthol having an optical rotation of and amelting point of 425 C. is isolated by means of ortho-phosphoric acidaccording to the process of U. S. Patent No. 1,932,131.

Example 2 15 parts of a mixture of copper, nickel and magnesiumcarbonates containing the metals in the ratio Cu:Ni:Mg=10:10:1 areheated in an open pan to a temperature of 300-350 C. until evolution ofcarbon dioxide ceases. The resulting mixture of oxides is washed withdistilled water until the washings have a pH value of 10.0 and is thendried and reduced with hydrogen at 240 C. The catalyst thus prepared isadded to a solution of 100 parts of laevo-piperitone in 200 parts ofmethanol of 94 per cent. strength and the whole is treated with hydrogenin an autoclave under a pressure of 100 lbs. per square inch and at atemperature of 25 C. until absorption of hydrogen ceases, which is thecase when 1 molecular proportion of hydrogen has been absorbed. Theliquid is separated from the catalyst and the methanol is then removedby distillation under reduced pressure. The menthone which remains isagain mixed with the catalyst and hydrogenation is continued until afurther molecular proportion of hydrogen has been absorbed.

The hydrogenation product is further treated as described in Example 1for the isolation of dextro-neoisomenthol and for the production fromthis body of laevo-menthol.

Example 3 10 parts of Mond nickel are dissolved in an excess of nitricacid, the solution is evaporated to dryness and the residue is ignitedto nickel oxide. The oxide is washed with distilled water until thewashings are neutral, dried and reduced at 280- 300 C. with hydrogen.

100 parts of pure laevo-piperitone are hydrogenated in presence of thecatalyst thus prepared under a hydrogen pressure of 100 lbs. per squareinch and at a temperature of 100 C., absorption of hydrogen ceasing atthe menthone stage. The menthone is separated by decantation and furtherhydrogenated and worked up to yield pure laevo-menthol as described inExample 1.

Having thus described the nature of the said invention and the bestmeans I know of carrying the same into practical effect, I claim:

1. A process for converting laevo-piperitone in optically activehydrogenation products thereof without appreciable racemisation, whichcomprises hydrogenating the laevo-piperitone at a temperature belowabout 140 C. in the presence of a hydrogenation catalyst having areaction corresponding with a pH-value between and as determined byextraction of the catalyst with water and measurement of the pH-value ofthe tween 5 and 10 as determined by extraction of the a catalyst withwater and measurement of the pH- value of the extract water.

3. A process for converting laevo-piperitone into optically activementhones without appreciable racemisation, which compriseshydrogenating the laevo-piperitone at a temperature below about 140 C.in the presence of a hydrogenation catalyst having a reactioncorresponding with a pH-value between 5 and 10 as determined byextraction of the catalyst with water and measurement of the pH-value ofthe extract water, the hydrogenation being discontinued whenapproximately two atoms of hydrogen have been absorbed per one moleculeof piperitone.

4. A process for converting laevo-piperitone into optically activementhones without appreciable racemisation, which compriseshydrogenating the laevo-piperitone at a temperature below about 140 C.in the presence of an organic solvent containing oxygen and having adielectric constant of at least about and in the presence of ahydrogenation catalyst having a reaction corresponding with a pH-valuebetween 5 and 10 as determined by extraction of the catalyst with waterand measurement of the pH-value of the extract water, the hydrogenationbeing discontinued when approximately two atoms of hydrogen have beenabsorbed per one molecule of piperitone.

5. A process for converting laevo-piperitone into optically activementhols without appreciable racemisation, which comprises hydrogenatingthe laevo-piperitone at a temperature below about 140 C. untilsubstantially no more hydrogen is absorbed in the presence of ahydrogenation catalyst having a reaction corresponding with a pH- valuebetween 5 and 10 as determined by extraction of the catalyst with waterand measurement of the pH-value of the extract water.

6. A process for converting laevo-piperitone into optically activementhols without appreciable racemisation, which comprises hydrogenatingthe laevo-piperitone at a temperature below about 140 C. in the presenceof an organicsolvent containing oxygen and having a dielectric constantof atleast about 15 and in the presence of a hydrogenation catalysthaving a reaction corresponding with a pH-value between 5 and 10 asdetermined by extraction of the catalyst with water and measurement ofthe pH-value of the extract water, the hydrogenation being discontinuedwhen approximately two atoms of hydrogen have been absorbed per onemolecule of piperitone, then removing the solvent and continuing thehydrogenation further in absence of the solvent until substantially nomore hydrogen is absorbed.

7. A process for converting laevo-piperitone substantially free frompiperitone racemate and having an optical rotation of not less thanabout [01119: minus 60 into optically active hydrogenation productsthereof without appreciable racemisation, which comprises hydrogenatingthe laevo-piperitone at a temperature below about C. in the presence ofa hydrogenation catalyst having a reaction corresponding with a pH-valuebetween 5 to 10 as determined by extraction of the catalyst with waterand measurement of the pH-value of the extract water.

8. A process for converting laevo-piperitone substantially free frompiperitone racemate and having an optical rotation of not less thanabout into optically active hydrogenation products thereof withoutappreciable racemisation, which comprises hydrogenating thelaevo-piperitone at a temperature below about 140 C. in the presence ofan organic solvent containing oxygen and having a dielectric constant ofat least about 5 and in the presence of a hydrogenation catalyst havinga reaction corresponding with a pH-value between 5 and 10 as determinedby extraction of the catalyst with water and measurement of the pH-valueof the extract water.

9. A process for converting laevo-piperitone substantially free frompiperitone racemate and having an optical rotation of not less thanabout [or "3: minus 60 into optically active menthones Withoutappreciable racemisation, which comprises hydrogenating thelaevo-piperitone at a temperature below about 140 C. in the presence ofa hydrogenation catalyst having a reaction corresponding with a pH-valuebetween 5 and 10 as determined by extraction of the catalyst with waterand measurement of the pH-value of the extract water, the hydrogenationbeing discontinued when approximately two atoms of hydrogen have beenabsorbed per one molecule of piperitone.

10. A process for converting laevo-piperitone substantially free frompiperitone racemate and having an optical rotation of not less thanabout into optically active menthones without appreciable racemisation,which comprises hydrogenating the laevo-piperitone at a temperaturebelow about 140 C, in the presence of an organic solvent containingoxygen and having a dielectric constant of at least about 15 and in thepresence of a hydrogenation catalyst having a reaction correspondin witha pI-I-value between 5 and 10 as determined by extraction of thecatalyst with water and measurement of the pI-I-value of the extractwater, the hydrogenation being discontinued when approximately two atomsof hydrogen have been absorbed per one molecule of piperitone.

11. A process for converting laevo-piperitone substantially free frompiperitone racemate and having an optical rotation of not less thanabout [041%9: minus 60 into optically active menthols withoutappreciable racemisation, which comprises hydrogenating thelaevo-piperitone at a temperature below about 140 C. until substantiallyno more hydrogen is absorbed in the presence of a hydrogenation catalysthaving a reaction corresponding with a pH-value between and 10 asdetermined by extraction of the catalyst with water and measurement ofthe pH-value of the extract water.

12. A process for converting laevo-piperitone substantially free frompiperitone racemate and having an optical rotation of not less thanabout [051% minus 60 into optically active menthols without appreciableracemisation, which comprises hydrogenating the laevo-piperitone at atemperature below about 140 C. in the presence of an organic solventcontaining oxygen and having a dielectric constant of at least about andin the presence of a hydrogenation catalyst having a reactioncorresponding with a pH-value between 5 and 10 as determined byextraction of the catalyst with water and measurement of the pH-value ofthe extract water, the hydrogenation being discontinued whenapproximately two atoms of hydrogen have been absorbed per one moleculeof piperitone, then removing the solvent and continuing thehydrogenation further in absence of the solvent until substantially nomore hydrogen is absorbed.

13. A process for converting laevo-piperitone substantially free frompiperitone racemate and having an optical rotation of not less thanabout [a]? minus 60 into optically active menthols without appreciableracemisation, which comprises hydrogenating the laevo-piperitone at atemperature below about 140 C. until substantially no more hydrogen isabsorbed in the presence of a hydrogenation catalyst having a reactioncorresponding with a pH-value between 5 and 10 as determined byextraction of the catalyst with water and measurement of the pH-value ofthe extract water and isolating dextro-neoisomenthol from the product ofthe hydrogenation.

14. A process for converting laevo-piperitone substantially free frompiperitone racemate and having an optical rotation of not less thanabout [041 3 minus 60 into optically active menthols without appreciableracemisation, which comprises hydrogenating the laevo-piperitone at atemperature below about 140 C. in the presence of an organic solventcontaining oxygen and having a dielectric constant of at least about 15and in the presence of a hydrogenation catalyst having a reactioncorresponding with a pH-value between 5 and 10 as determined byextraction of the catalyst with water and measurement of the pH-value ofthe extract water, the hydrogenation being discontinued whenapproximately two atoms of hydrogen have been absorbed per one moleculeof piperitone, then removing the solvent and continuing thehydrogenation further in absence of the solvent until substantially nomore hydrogen is absorbed and isolating dextro-neoisomenthol from theproduct of the hydrogenation.

15. A process for preparing laevo-menthol from laevo-piperitonesubstantially free from piperitone racemate and having an opticalrotation of not less than about which comprises hydrogenating thelaevo-piperitone at a temperature below about C. until substantially nomore hydrogen is absorbed in the presence of a hydrogenation catalysthaving a reaction corresponding with a pH-value between 5 and 10 asdetermined :by extraction of the catalyst with water and measurement ofthe pH-value of the extract water, isolating dextroneoisomenthol fromthe product of the hydrogenation, subjecting the dextro-neoisomenthol toisomerisation 'to produce an optically active mixture containinglaeVo-menthol and isolating laevo-menthol from this mixture.

16. A process for preparing laevo-menthol from laeVo-piperitonesubstantially free from piperitone racemate and having an opticalrotation of not less than about which comprises hydrogenating thelaevopiperitone at a temperature below about 140 C. in the presence ofan organic solvent containing oxygen and having a dielectric constant ofat least about 15 in the presence of a hydrogenation catalyst having areaction corresponding with a pH-value between 5 and 10 as determined byextraction of the catalyst with water and measurement of the pH-value ofthe extract water, the hydrogenation being discontinued whenapproximately two atoms of hydrogen have bgeen absorbed per one moleculeof piperitone, then removing the solvent and continuing thehydrogenation further in absence of the solvent until substantially nomore hydrogen is absorbed, isolating dextro-neoisomenthol from theproduct of the hydrogenation, subjecting the dextroneoisomenthol toisomerisation to produce an optically active mixture containinglaevo-menthol and isolating laevo-menthol from this mixture.

17. A process for preparing laevo-menthol from laevo-piperitonesubstantially free from piperitone racemate and having an opticalrotation of not less than about which comprises hydrogenating thelaevo-piperitone at a temperature below about 140 C. until substantiallyno more hydrogen is absorbed in the presence of a hydrogenation catalysthaving a reaction corresponding with a pH-value between 5 and 10 asdetermined by extraction of the catalyst with water and measurement ofthe pH-value of the extract water, isolating dextroneoisomenthol fromthe product of the hydrogenation, agitating the dextro-neoisomenthol inpresence of a hydrogenating catalyst at a raised temperature below about140 0., thereby forming an optically active mixture containinglaevomenthol, and isolating laevo-menthol from this mixture.

18. A process for preparing laevo-menthol from laevo-piperitonesubstantially free from piperitone racemate and having an opticalrotation of not less than about [04]: minus 60 which compriseshydrogenating the laevo-piperitone at a temperature below about 140 C.,in.

the presence of an organic solvent containing oxygen and having adielectric constant of at least about 15 and in the presence of ahydrogenation catalyst having a reaction corresponding with a pH-valuebetween and as determined by extraction of the catalyst with water andmeasurement of the pH-value of the extract Water, the hydrogenationbeing discontinued when approximately two atoms of hydrogen have beenabsorbed per one molecule of piperitone, then removing the solvent andcontinuing the hydrogenation further in absence of the solvent untilsubstantially no more hydrogen is absorbed, isolatingdextro-neoisomenthol from the product of the hydrogenation, agitatingthe dextroneoisomenthol in presence of a hydrogenating catalyst at araised temperature below about 140 0., thereby forming an opticallyactive mix ture containing laevo-m-enthol, laevo-menthol from thismixture.

19. A process for preparing laevo-menthol from laevo-piperitonesubstantially free from piperitone racemate and having an opticalrotation of not less than about and isolating [a]=minus 60 whichcomprises hydrogenating the laevopiperitone at a temperature below about140 C. until substantially no more hydrogen is absorbed in the presenceof a hydrogenation catalyst hav- 0 phoric acid to form a phosphoric acidaddition product of the laevo-menthol contained therein, isolating thisphosphoric acid addition product, decomposing it to liberatelaevo-menthol and recovering the liberated laevo-menthol.

20. A process for preparing laevo-menthol from laevo-piperitonesubstantially free from piperitone racemate and having an opticalrotation of not less than about [611% minus which compriseshydrogenating the laevo-piperitone at a temperature below about C. inthe presence of an organic solvent containing oxygen and having adielectric constant of at least about 15 and in the presence of ahydrogenation catalyst having a reaction corresponding with a pH-valuebetween 5 and 10 as determined by extraction of the catalyst with waterand measurement of the pI-I-value of the extract water, thehydrogenation being discontinued when approximately two atoms ofhydrogen have been absorbed pe' one molecule of piperitone, thenremoving the solvent and continuing the hydrogenation iurther in absenceof the solvent until substantially no more hydrogen is absorbed,reacting the hydrogenation product with ortho-phosphoric acid to form aphosphoric acid addition product of the dextro-neoisomenthol containedtherein, isolating this phosphoric acid addition product, decomposing itto liberate dextro-neoisomenthol, agitating the dextro-neoisomenthol inpresence of a hydrogenating catalyst at a raised temperature below about140 0., thereby forming an optically active mixture containinglaevo-menthol, reacting this mixture with ortho-phosphoric acid to forma phosphoric acid addition product of the laevo-menthol containedtherein, isolating this phosphoric acid addition product, decomposing itto liberate laevo-menthol and recovering the liberated laevo-menthol.

' JOHN WILLIAM BLAGDEN.

WALTER. EDWARD HUGGETT,

